The present invention relates to novel histidine derivatives and to a process for their preparation. The invention also relates to cosmetic or dermatological compositions comprising these compounds. The invention also relates more particularly to the use of these compounds as anti-free-radical agents.
Solar radiation, heat, atmospheric pollution and, in particular, smoke and tobacco are known to lead to the formation of free radicals. They originate to a large extent from molecular oxygen.
Mention may be made of the following free radicals:
singlet oxygen, which is highly oxidizing, highly toxic and has a very short lifetime, produced by the excitation of molecular oxygen with photons of light;
the superoxide anion radical, produced by the addition of an electron to oxygen and capable of giving rise to the production of highly reactive hydroxyl radicals;
the hydroxyl radical, which is highly oxidizing and the most toxic to cells.
The formation of these radical species leads in particular to oxidation of the lipids in the skin.
Live cells, in particular those in the skin, the scalp and certain mucous membranes, are particularly sensitive to these free radicals, which is reflected in accelerated ageing of the skin, with a complexion lacking radiance and early formation of wrinkles and fine lines, and also by a reduction in the vigour and a dull appearance of the hair.
It is thus seen that it is particularly important to protect the skin, the hair and the mucous membranes against these free radicals.
It is known that certain antioxidants are capable of inhibiting the formation of free radicals.
Thus, carnosine, or N-xcex2-alanyl-L-histidine, which is a natural dipeptide found in the muscles of many vertebrates, is known for its anti-free-radical activity, in particular its activity against singlet oxygen (E. Decker and H. Faraji, JAOCS, vol. 67, No. 10, 650-652, 1990). Its use as an antioxidant or as anti-free-radical agent in cosmetics is also known from patent application WO-A-92/09298. However, when in contact with the skin, carnosine displays degradation problems caused by the enzymes present in the skin and in particular proteases, which leads to a substantial loss of its activity.
Carnosine derivatives are also known, such as, for example, the N-acyl carnosine derivatives described in patent FR-C-2,496,660. Products with antioxidant activity, obtained by coupling fatty acids and carnosine and used in cosmetic preparations, have been described in patent application FR-A-2,668,365. However, such carnosine derivatives also have the same problem of instability in the presence of the enzymes present in the skin.
The Applicant has discovered, unexpectedly, novel histidine derivatives which display greater stability on contact with the enzymes present in the skin, and in particular proteases, than do the known derivatives of the prior art, while at the same time having good anti-free-radical activity and in particular having a good property of efficacy in the deactivation of singlet oxygen. They can thus be used in cosmetics and pharmacy: they are easy to apply to the skin.
The Applicant has found that such results can be obtained with lipodipeptide histidine derivatives containing a carbamate function.
A subject of the invention is thus novel histidine derivatives corresponding to the general formula (I) below: 
in which:
R denotes a linear or branched, saturated or unsaturated alkyl radical containing from 6 to 22 carbon atoms,
n is an integer from 1 to 16,
Q+ represents H+ or an organic or inorganic cation, and the addition salts with an acid.
According to the invention, R preferably denotes a linear or branched, saturated alkyl radical containing from 8 to 18 carbon atoms and n is an integer ranging from 1 to 11.
The organic cation can be chosen from ammoniums containing a residue chosen from basic amino acids such as lysine or arginine, or alternatively from amino alcohols such as glucamine, N-methylglucamine or 3-amino-1,2-propanediol.
The inorganic cation can be chosen from alkali metal or alkaline-earth metal cations such as Na+ or K+, or can be the NH4+ ion.
The addition salts with an acid are chosen, for example, from the hydrochlorides, hydrobromides, sulphates, tartrates and acetates.
The compounds of formula (I) containing an asymmetric carbon in their structure comprise the compounds of D configuration, of L configuration or of D, L configuration.
Among the preferred compounds corresponding to the general formula (I), mention may be made in particular of:
N-octyloxycarbonyl-xcex2-alanyl-L-histidine,
N-dodecyloxycarbonyl-xcex2-alanyl-L-histidine,
N-2-ethylhexyloxycarbonyl-xcex2-alanyl-L-histidine hydrochloride,
N-hexadecyloxycarbonyl-xcex2-alanyl-L-histidine.
A subject of the present invention is also the process for preparing the compounds of formula (I).
This process consists in reacting, in an inert solvent, a compound of formula (II) 
X representing a halogen atom, in particular a chlorine atom, or a radical derived from an azole, in particular a radical originating from an imidazole such as that of formula (III): 
and R having the same meaning given in formula (I) above,
either (A) with carnosine,
or (B), in a first step, with an amino acid of formula:
H2Nxe2x80x94(CH2)nxe2x80x94COOH
to form a compound of formula (IV) below: 
xe2x80x83R and n having the same meanings as those given in formula (I) defined above,
and, in a second step, in reacting in histidine with the compound of formula (IV) in the presence of a coupling agent.
The term xe2x80x9ccoupling agentxe2x80x9d refers to any compound capable of substituting the OH group in the compound of formula (IV), and then of being subsequently substituted with histidine. Coupling agents are mentioned in xe2x80x9cAdvanced Organic Chemistry, J. March, 3rd edition, 1985, page 372xe2x80x9d. 2-(5-Norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate can be used in particular as a coupling agent.
The starting histidine and carnosine, each containing an asymmetric carbon, are used in the pure optical form or as a mixture (D; L; D,L) depending on the desired optical form of the compound of formula (I)
Dichloromethane, 1,2-dichloroethane, 1,1,1-trichloroethane, chloroform, acetonitrile, toluene, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, cyclohexane, water or a mixture of these solvents can be used as inert solvent.
The reaction is carried out at a temperature preferably between xe2x88x9210xc2x0 C. and +40xc2x0 C., and more preferably between 20xc2x0 C. and 30xc2x0 C.
The reaction can be carried out in the presence of a base. This can be chosen from alkali metal or alkaline-earth metal hydroxides, sodium hydrogen carbonate, alkali metal alkoxides, alkaline hydrides and tertiary amines such as pyridine or triethylamine. Sodium hydrogen carbonate is preferably used.
The present invention also relates to a composition comprising, in a physiologically acceptable medium, a compound of formula (I) as defined above.
The composition comprising the said compound can be, in particular, in the form of a cosmetic or pharmaceutical composition comprising a cosmetically or pharmaceutically acceptable medium, respectively.
In the compositions according to the invention, the compounds of formula (I) are generally present at a concentration of from 0.01% to 15% by weight, and preferably from 0.1% to 5% by weight, relative to the total weight of the composition.
These compositions can be prepared according to the usual methods known to those skilled in the art. They can be in the form of a lotion, a gel, a water-in-oil or oil-in-water emulsion, a microemulsion, a milk, a cream, a powder, pastes, a solid stick, a spray or an aerosol mousse.
A subject of the invention is also the use of the compounds of formula (I) as anti-free-radical agents, and in particular as anti-free-radical agents for deactivating singlet oxygen, and in particular in a cosmetic or pharmaceutical composition.
The invention also relates to the use of the compounds of formula (I) in a cosmetic or pharmaceutical composition for treating keratin substances against the effects of ageing.
The terms xe2x80x9ckeratin substancesxe2x80x9d means the skin, head hair, the nails, other body hairs and mucous and semi-mucous membranes such as the lips.
The Applicant has also discovered, surprisingly, that the compounds of formula (I) constitute anionic amphiphilic lipids which can form stable lipid vesicles.
In a known manner, lipid vesicles are generally characterized by a lipid membrane consisting of substantially concentric leaflets containing one or more multimolecular layers encapsulating a liquid phase. This liquid phase is commonly an aqueous phase. These vesicles are prepared, in a known manner, in the form of a dispersion in an aqueous phase. A non-limiting list of various preparation methods will be found in xe2x80x9cLes liposomes en biologie cellulaire et pharmacologiexe2x80x9d [Liposomes in cellular biology and pharmacology]xe2x80x94INSERM publicationsxe2x80x94John Libley, Eurotext, 1987, pages 6 to 18.
A subject of the present invention is thus an aqueous dispersion of lipid vesicles comprising a lipid membrane formed from at least one compound of formula (I) as defined above.
The lipid vesicles in accordance with the invention preferably contain a lipid membrane encapsulating an aqueous phase.
A subject of the present invention is also a cosmetic or pharmaceutical composition containing an aqueous dispersion of lipid vesicles comprising a lipid membrane formed from at least one compound of formula (I).
Another subject of the invention also consists in using the compounds of formula (I) as defined above as amphiphilic lipids capable of forming lipid vesicles.
According to the invention, any ionic and/or nonionic amphiphilic lipid capable of forming stable vesicles, alone or as a mixture with additives whose function is to reduce the permeability of the vesicle membranes and to improve their stability, can be used as a mixture with the compounds of formula (I) to constitute lipid membranes of the vesicles according to the invention. The lipid phase constituting the membranes of the vesicles in the dispersion according to the invention can thus comprise, in a known manner, at least one amphiphilic lipid chosen from the group formed by nonionic amphiphilic lipids and ionic amphiphilic lipids.
The nonionic amphiphilic lipids used with the compounds of formula (I) to form the lipid membrane of the vesicles according to the invention can be chosen from:
(1) the glycerol derivatives of formula:
R10Oxe2x80x94[xe2x80x94C3H5xe2x80x94(OH)Oxe2x80x94]qxe2x80x94H
xe2x80x83in which:
xe2x80x94C3H5(OH)Oxe2x80x94 is represented by the following structures, taken as a mixture or separately: 
q is an average statistical value between 2 and 6;
R10 represents:
(a) a linear or branched aliphatic chain containing from 12 to 18 carbon atoms;
(b) a residue R11CO, in which R11 is a linear or branched aliphatic C11-C17 radical;
(c) a residue R12xe2x80x94[xe2x80x94OC2H3(R13)xe2x80x94]xe2x80x94, in which:
R12 can take the meaning (a) or (b) given for R10;
OC2H3(R13)xe2x80x94 is represented by the following structures, taken as a mixture or separately: 
xe2x80x83in which R13 takes the meaning (a) given for R10;
(2) polyoxyethylenated fatty alcohols and polyoxyethylenated sterols,
(3) optionally polyoxyethylenated polyesters;
(4) natural or synthetic glycolipids;
(5) oxyethylenated polyglyceryl stearate;
(6) the glycerol derivatives described in PCT patent application No. 92/08685 and corresponding to formula (V):
HOCH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94Oxe2x80x94[xe2x80x94CH2xe2x80x94CH(R14)xe2x80x94Oxe2x80x94]pxe2x80x94Hxe2x80x83xe2x80x83(V)
xe2x80x83in which R14 represents a linear C14 to C18 alkyl radical or a group xe2x80x94CH2Y in which Y is xe2x80x94OR15, R15 representing a linear C10-C18, and preferably C16, alkyl radical and p represents an average statistical value greater than 1 and not more than 3, and, in addition, when R14 is xe2x80x94CH2Y, p can also represent an integer equal to 2; and
(7) fatty acid esters and ethers of xcex1-butylglucoside which either can be mixtures of different fatty acid esters of xcex1-butylglucoside and/or mixtures of different fatty acid ethers of xcex1-butylglucoside, in which the various fatty chains contain a similar number of carbon atoms relative to each other (for example differing by 1 or 2), or can be mixtures of the same fatty acid mono-, di-, tri- or polyesters of xcex1-butylglucoside and/or mixtures of the same fatty acid of mono-, di-, tri- or polyethers of an xcex1-butylglucoside.
The fatty acid esters and ethers of xcex1-butylglucoside used according to the invention preferably contain a fatty chain containing from 8 to 24 carbon atoms, more preferably from 12 to 22 carbon atoms and more particularly from 14 to 18 carbon atoms.
Mention may be made, for example, of lauric (C12), myristic (C14), palmitic (C16), stearic (C18) and behenic (C22) acid esters and ethers of xcex1-butylglucoside. A mixture of palmitic acid mono- and diester of xcex1-butylglucoside is used more particularly.
The fatty acid esters and ethers of xcex1-butylglucoside in accordance with the invention can be prepared from xcex1-butylglucoside obtained according to the enzymatic manufacturing process described in patent application FR-A-2,680,373, which consists in placing butanol in contact with starch, maltodextrins or maltose in the presence of a purified enzymatic preparation which has xcex1-transglucosylation activity. The fatty acid esters and ethers of xcex1-butylglucoside can be synthesized by reacting the corresponding fatty acid or fatty acid mixture with xcex1-butylglucoside according to standard processes.
The ionic amphiphilic lipids used in combination with the compounds of formula (I) to form the membrane of the vesicles according to the invention can be chosen from:
(1) the following anionic amphiphilic lipids:
natural phospholipids such as egg or soybean lecithin, sphingomyelin, phosphatidylserine, dipalmitoylphosphatidylcholine and hydrogenated lecithins, chemically or enzymatically modified phospholipids and synthetic phospholipids;
the anionic compounds of formula (VI): 
xe2x80x83in which:
R16 represents a C7-C21 alkyl or alkenyl radical,
R17 represents a saturated or unsaturated C7-C31 hydrocarbon-based radical,
M represents H, Na, K, NH4 or a substituted ammonium ion derived from an amine;
anionic compounds such as phosphoric esters of a fatty alcohol, in particular dicetyl phosphate and dimyristyl phosphate in acidic form or in the form of alkaline salts, heptylnonylbenzenesulphonic acid, cholesteryl hydrogen sulphate or cholesteryl hydrogen phosphate, as well as the alkaline salts thereof, lysolecithins, alkyl sulphates such as sodium cetyl sulphate, gangliosides, monosodium and disodium acylglutamates, and in particular the monosodium and disodium salts of N-stearoylglutamic acid, the sodium salts of phosphatidic acid, phosphoaminolipids and natural phospholipids,
(2) the following cationic amphiphilic lipids:
cationic compounds of formula (VII):
(R18)(R19)N+(R20)(R21)Xxe2x88x92xe2x80x83xe2x80x83(VII)
xe2x80x83in which R18 and R19, which may be identical or different, represent C12-C20 alkyl radicals and R20 and R21, which may be identical or different, represent C1-C4 alkyl radicals,
long-chain amines and the quaternary ammonium derivatives thereof, long-chain amino alcohol esters and the salts and quaternary ammonium derivatives thereof,
polymerizable lipids, as described by Riingsdorf et al. in xe2x80x9cAngewandte Chemiexe2x80x9d, vol. 27, No. 1, January 1988, pages 129-137.
It is possible, in a known manner, to incorporate into the lipid phase constituting the lipid membrane of the vesicles of the invention at least one additive whose main function is to reduce the permeability of the vesicles, to prevent their flocculation and fusion and to increase the degree of encapsulation.
According to a preferred embodiment of the invention, at least one additive preferably chosen from the group formed by:
sterols and in particular phytosterols and cholesterol,
long-chain alcohols and diols,
long-chain amines and the quaternary ammonium derivatives thereof, can be added to the lipid phase.
These additives may optionally have cosmetic and/or dermopharmaceutical activity. This is the case, for example, for cholesterol.
The aqueous continuous phase of the vesicle dispersion according to the invention can consist of water or a mixture of water and at least one water-miscible solvent such as C1-C7 alcohols and C2-C5 alkyl polyols. This aqueous phase can also contain compounds in solution, such as sugars, organic or inorganic salts or polymers. It can also contain a dispersion of droplets of a water-immiscible liquid which the vehicles stabilize, such that it is not necessary to introduce an emulsifier for this stabilization. This immiscible liquid can be chosen from the group formed by animal or plant oils, natural or synthetic essential oils, hydrocarbons, halocarbons, silicones, inorganic acid esters of an alcohol, ethers and polyethers. Examples of water-immiscible liquids are mentioned in patent application EP-A-455,528.
The compositions containing the compounds according to the invention can also contain, in a known manner, one or more active compounds with cosmetic and/or pharmaceutical activity which, depending on their solubility characteristics, can have different localizations. For example, in the case of vesicle dispersions containing an encapsulated aqueous phase, if the active agents are liposoluble, they can be present in the lipid phase constituting the leaflet(s) of the vesicles or in the droplets of water-immiscible liquid stabilized by the vesicles. If the active agents are water-soluble, they can be present in the encapsulated aqueous phase of the vesicles or in the continuous aqueous phase of the dispersion. If the active agents are amphiphilic, they distribute themselves between the lipid phase and the encapsulated aqueous phase with a partition coefficient which varies depending on the nature of the amphiphilic active agent and the respective compositions of the lipid phase and of the encapsulated aqueous phase. In general, the active agents are placed in the lipid phase of the leaflets and/or in the phase encapsulated by the leaflets.
The compositions according to the invention can also comprise, in a known manner, formulation additives which have neither any intrinsic pharmaceutical or cosmetic activity, but which are useful for formulating the compositions. Among these additives, mentioned may be made, for example, of gelling agents, polymers, preserving agents, dyes, opacifiers and fragrances.
The cosmetic or pharmaceutical compositions according to the invention can be, in particular, in the form of shampoos or conditioners, cleansing compositions, skincare or haircare creams, antisun compositions, aftershave creams or mousses, body deodorants, compositions for oral use, hair dye compositions or make-up compositions, for example.
The examples given below, for illustrative purposes and without any limitation at all, will make it possible to gain a better understanding of the invention.